Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
A Combination of Visible-Light Organophotoredox Catalysis and Asymmetric Organocatalysis for the Enantioselective Mannich Reaction of Dihydroquinoxalinones with Ketones Jaume Rostoll-Berenguer,† Gonzalo Blay,† M. Carmen Muñoz,‡ José R. Pedro,*,† and Carlos Vila*,† †
Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100 Burjassot, València, Spain Departament de Física Aplicada, Universitat Politècnica de València, Camino de Vera s/n, 46022 València, Spain
‡
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S Supporting Information *
ABSTRACT: An enantioselective photooxidative Mannich reaction of dihydroquinoxalinones with ketones by the merger of organophotoredox and asymmetric organocatalysis is described. This protocol features very mild reaction conditions using simple and cheap catalysts (Eosin Y and (S)-Proline) for the synthesis of chiral quinoxaline derivatives with good to high yields (up to 94%) and excellent enantioselectivities (up to 99% ee).
T
Scheme 1. Enantioselective Photooxidative Mannich Reaction
he employment of visible-light photoredox catalysis has become a hot topic in synthetic chemistry in the past decade, due to its significant advantages such as low cost, safety, renewability, abundance, and environmental friendliness.1,2 On the other hand, control of chirality is one of the guiding principles in the chemical community over recent decades. One of the main objectives of the organic chemistry is exploiting the full potential of synthetic chemistry to create and control chiral structures with different types of functions.3 In this context, asymmetric catalysis provides vast opportunities for an economical and efficient access to chiral compounds in enantiomerically pure form.4 Therefore, interfacing visible-light photochemical activation with asymmetric catalysis has provided new opportunities for the development of synthetic methods for efficient, convenient, and green synthesis of nonracemic chiral molecules.5 In recent years, several examples of the combination of visible-light photoredox catalysts and organocatalysts have been described for the α- and βfunctionalization of carbonyl compounds6 and for the C(sp3)−H α-functionalization of amines.7 The enantioselective synthesis of chiral amines is, generally, a remarkable research area owing to the importance of chiral nitrogen-containing compounds for medicinal, pharmaceutical, and agrochemical chemistry.8 In this context, since the pioneering report of List,9 the organocatalytic asymmetric Mannich reaction represents a powerful methodology for the synthesis of chiral amines.10 Besides, the enantioselective oxidative Mannich reaction that includes C(sp3)−H αfunctionalization of amines with carbonyl compounds has been described recently.11 However, only two examples of the combination of visible-light photoredox catalysts and asymmetric catalysis for the oxidative Mannich reaction of amines (tetrahydroisoquinolines) and cyclic ketones have been described by Luo12 and Rueping,13 independently (Scheme 1). Therefore, our attention is focused on developing a suitable catalytic system for accomplishing the enantioselective C© XXXX American Chemical Society
(sp3)−H α-functionalization of other amines different from tetrahydroisoquinolines. In particular, dihydroquinoxalinones constitute a prevailing scaffold frequently found in many biologically active natural and synthetic products (Figure 1).
Figure 1. Selected bioactive chiral dihydroquinoxalinones.
Many examples are used as pharmaceuticals, including antiviral compounds, used for the treatment of HIV,14 anticancer compounds,15 cholesteryl ester transfer protein inhibitors,16 antiinflammatory compounds,17 antitumor agents,18 and also as agrochemicals.19 However, enantioselective approaches to the synthesis of chiral dihydroquinoxalin-2-ones are scarce and limited to catalytic asymmetric hydrogenations of quinoxalinones.20,21 In view of the few examples of the catalytic Received: June 21, 2019
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DOI: 10.1021/acs.orglett.9b02157 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
consumed and the formation of the cyclic imine quinoxalin-2one was observed. Then, acetone 2a (1 mL) and (S)-proline (20 mol %) were added to the reaction mixture and stirred for 80 h under darkness, in order to avoid the over-oxidation products. The desired product 3aa was isolated with the same enantiomeric excess (99% ee), but much better yield (77%, entry 2). Next, we evaluated the light sources (entries 2−4), observing that the oxidation was much faster, only 4 h, under blue LED irradiation although the yield was lower (59%) (entry 4). Other photocatalysts (Ru(bpy) 3 Cl2 , Fukuzumi photocatalyst, and Eosin Y) were evaluated (entries 5−7), obtaining similar reaction times, yields, and enantioselectivities. In order to develop a more cost-effective and green protocol, we decided to continue the optimization using Eosin Y as the photocatalyst. Then, different solvents such as toluene, CHCl3, DMSO, and DMF were evaluated (entries 8−11). In toluene and CHCl3, the oxidation step was very slow, while, with DMSO and DMF, the oxidation step was similar to the case of CH3CN. Because the enantioselective Mannich reaction was faster in DMF (2 days, entry 11), we continued the optimization with this solvent. Lowering the photocatalyst to 2 mol % was beneficial for both steps, obtaining product 3aa with 74% yield and 99% ee after 21 h (entry 12). Decreasing the amount of acetone to 10 equiv (entry 13) was detrimental for the speed of the asymmetric Mannich reaction (3 days), and product 3aa was isolated with 82% yield and 96% ee. Finally, several control experiments were carried out. When the reaction was carried out under darkness (entry 14), we did not observe the oxidation of dihydroquinoxalin-2-one 1a to quinoxalin-2-one after 5 days. While the reaction proceeded without a catalyst (entry 15), giving the corresponding oxidation of dihydroquinoxalin-2-one, it was very slow (102 h). The subsequent addition of acetone and (S)-proline led to the formation of product 3aa with 73% yield and 99% ee. Moreover, we performed the enantioselective Mannich reaction using the imine (quinoxalin-2(1H)-one) as the electrophile (entry 16) obtaining good yield and excellent enantioselectivity (99% ee). Once we had the optimized reaction conditions (entry 12), we evaluated the scope of the enantioselective oxidative Mannich reaction, as is shown in the Scheme 2. First we evaluated the effect of the protecting group at the nitrogen of the amide of dihydroquinoxalin-2-one 1. The reaction tolerates several groups at the nitrogen atom, such as methyl, benzyl, allyl, or CH2CO2Me, affording the corresponding chiral quinoxalines 3 with good yields and excellent enantioselectivities. These results are remarkable, because only the oxidation of the endocyclic CH2 was observed (3ba−3ea). 3,4Dihydroquinoxalin-2-one (1) bearing electron-donating (Me, OMe) or electron-withdrawing (CF3, F, CO2H) groups on the aromatic ring furnished the corresponding chiral ketones 3 in good yields (58−93%) and excellent enantioselectivities (97− 99% ee), regardless of the position or the electronic character of the substituents (3fa−3ma). Moreover, disubstituted 3,4dihydroquinoxalin-2-one also can be used obtaining the corresponding chiral quinoxalin-2-ones 3na and 3oa with excellent results in both yield and enantiomeric excess. We next explored the asymmetric Mannich reaction with other ketones such as butan-2-one 2b, 4-methylpentan-2-one 2c, or undecan-2-one 2d that afford the corresponding chiral products with excellent regio- and enantioselectivities, although with moderate yields (42−55%). Meanwhile, cyclic
asymmetric methodologies for the synthesis of such compounds, we envisioned that the corresponding quinoxalin-2one generated under mild conditions from 3,4-dihydroquinoxalin-2-one by a photocatalyzed oxidation might react with carbonyl compounds using asymmetric enamine catalysis giving a Mannich product. Hence, continuing with our interest in the synthesis of 1,4-dihydroquinoxalinones22 and the photoredox functionalization of cyclic amines,23 we described the development of a dual organocatalyst strategy for the enantioselective oxidative alkylation of dihydroquinoxalinones with ketones through an asymmetric Mannich reaction (Scheme 1). The enantioselective Mannich reaction between 3,4dihydroquinoxalin-2-one (1a) and acetone (2a) using (S)proline as an organocatalyst was selected as the model reaction (Table 1). The initial reaction using 1 mol % of Ir(ppy)3, Table 1. Optimization of the Reaction Conditionsa
entry 1d 2 3e 4f 5f 6f 7f 8f 9f 10f 11f 12f 13f,g 14h 15 16i
PC (%) Ir(ppy)3 (1%) Ir(ppy)3 (1%) Ir(ppy)3 (1%) Ir(ppy)3 (1%) Ru(bpy)3Cl2 (1%) Fukuzumi photocat. (5%) Eosin Y (5%) Eosin Y (5%) Eosin Y (5%) Eosin Y (5%) Eosin Y (5%) Eosin Y (2%) Eosin Y (2%) Eosin Y (5%) − −
solvent
t1 (h)
t2 (h)
yield (%)b
ee (%)c
MeCN MeCN MeCN MeCN MeCN MeCN
74 48 24 4 6 9
− 80 79 68 70 70
34 77 66 59 66 82
99 99 99 99 99 97
MeCN toluene CHCl3 DMSO DMF DMF DMF DMF DMF DMF
9 78 78 9 8 7 7 120 102 −
86 72 72 86 46 21 65 − 21 15
63 33 86 63 75 74 82 − 73 95
98 92 98 84 98 99 96 − 99 99
a Reaction conditions: A stepwise procedure where 1a (0.2 mmol) and photocatalyst (X mol %) were dissolved in 1 mL of solvent and stirred at rt under an air atmosphere and irradiation of 5 W white LEDs; upon consumption of the starting material, 2a (1 mL) and (S)proline (20 mol %) were added and stirred under darkness. bYield after purification by column chromatography. cThe enantiomeric excess was determined by HPLC analysis. dReaction conditions: 1a (0.2 mmol), 2a (1 mL), Ir(ppy)3 (1 mol %), (S)-proline (20 mol %) in 1 mL of MeCN at rt under an air atmosphere and irradiation of 5 W white LEDs. eUnder irradiation of a 11 W fluorescent bulb light. f Under irradiation of blue LEDs. g10 equiv of 2a were used. hReaction performed under darkness. iThe Mannich reaction was performed using quinoxalin-2(1H)-one as electrophile.
under irradiation of 5 W white LEDs, gave the corresponding chiral Mannich product 3aa with an excellent 99% ee, but low yield (34%, entry 1). In order to avoid possible side reactions in our system,24 we decided to attempt the activation of the substrates separately.13 Accordingly, dihydroquinoxalin-2-one (1a) and 1 mol % of Ir(ppy)3 were dissolved in 1 mL of CH3CN and stirred under irradiation of 5 W white LEDs and an air atmosphere. After 2 days, the starting material 1a was B
DOI: 10.1021/acs.orglett.9b02157 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Enantioselective Photooxidative Mannich Reactiona
Scheme 3. 5 mmol Reaction Scale Using Sun Light as Source of Irradiation
To elucidate the mechanism of the reaction, control experiments were conducted. The addition of TEMPO, a radical scavenger, inhibited the oxidation of 1, as well as when the reaction was run in the absence of oxygen. In addition, we performed a Stern−Volmer quenching experiment for the exicited Eosin Y photocatalyst with amine 1 (KSV = 79 M−1), suggesting that the reaction might proceed through an reductive quenching pathway.28 Therefore, under the irradiation of visible light and in the presence of Eosin Y and oxygen, dihydroquinoxalin-2-one 1 is oxidized to quinoxalin-2(1H)one, which reacts with the corresponding ketone affording the Mannich product 3. On the basis of the absolute configuration of 3aa (CCDC 1922649),29 we propose a plausible mechanism for the enantioselective oxidative Mannich reaction, as is shown in the Scheme 4. (S)-Proline reacts with acetone to Scheme 4. Plausible Stereochemical Pathway
form an enamine that attacks the Re face of the cyclic imine. The enantioselectivity is further controlled by hydrogen bonding between the proline carboxylic acid group and the cyclic imine.9,10 In summary, we have developed a photooxidative enantioselective Mannich reaction of 3,4-dihydroquinoxalin2-one derivatives with several ketones using visible-light organophotoredox and enamine catalysis.30 The corresponding chiral quinoxaline products were obtained with good yields and excellent enantioselectivities under very mild conditions. The reaction is scalable to 5 mmol scale using sun light. Our methodology shows a successfully combination of visible-light organophotoredox and enantioselective organocatalysis, in order to obtain interesting quinoxalinone derivatives.
a
The reaction was performed under sunlight irradiation.
ketones such as cyclohexanone and cyclopentanone were examined, affording the corresponding chiral Mannich products with excellent yields, but low diastereo- and enantioselectivities.25 Finally, the reaction tolerates functionalized ketones such 1-hydroxypropan-2-one or 1,1-dimethoxypropan-2-one, obtaining products 3ag and 3ah with excellent results. Interestingly, the 1-hydroxypropan-2-one gave exclusively the branched product, while the 1,1-dimethoxypropan-2one gave only the linear product. This is usual for proline catalyzed aldol26 or Mannich9 reactions, where the less substituted enamine is formed. In contrast to 2-butanone or 1,1-dimethoxypropan-2-one, the regioselectivity of enamine formation in the case of the hydroxyacetone is controlled by the π-donating OH group, which interacts with the π*-orbital of the CC bond thereby stabilizing the hydroxyl enamine.27 Gratifyingly, the practicability and scalability of this protocol were successfully demonstrated by performing the enantioselective oxidative Mannich reaction at 5 mmol scale using sun light and only 0.5 mol % of Eosin Y (Scheme 3). Under these conditions, the results were similar to those obtained on small scale (67% yield and 99% ee).
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02157. Complete experimental procedures and characterization of new products, 1H and 13C NMR spectra and HPLC traces for all compounds (PDF) C
DOI: 10.1021/acs.orglett.9b02157 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Accession Codes
For selected enantioselective reactions, see: (c) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094. (d) Bergonzini, G.; Schindler, C. S.; Wallentin, C.-J.; Jacobsen, E. N.; Stephenson, C. R. J. Chem. Sci. 2014, 5, 112. (e) Perepichka, I.; Kundu, S.; Hearne, Z.; Li, C.-J. Org. Biomol. Chem. 2015, 13, 447. (f) Wei, G.; Zhang, C.; Bureš, F.; Ye, X.; Tan, C.-H.; Jiang, Z. ACS Catal. 2016, 6, 3708. (g) Uraguchi, D.; Kinoshita, N.; Kizu, T.; Ooi, T. J. Am. Chem. Soc. 2015, 137, 13768. (h) Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre, P. Nature 2016, 532, 218. (i) Wang, C.; Qin, J.; Shen, X.; Riedel, R.; Harms, K.; Meggers, E. Angew. Chem., Int. Ed. 2016, 55, 685. (8) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications; Wiley-VCH: Weinheim, 2010. (9) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (10) (a) Córdova, A. Acc. Chem. Res. 2004, 37, 102. (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 2007, 5797. (c) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29. (d) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (11) (a) Zhang, G.; Zhang, Y.; Wang, R. Angew. Chem., Int. Ed. 2011, 50, 10429. (b) Zhang, J.; Tiwari, B.; Xing, C.; Chen, X.; Chi, Y. R. Angew. Chem., Int. Ed. 2012, 51, 3649. (c) Zhang, G.; Ma, Y.; Wang, S.; Kong, W.; Wang, R. Chem. Sci. 2013, 4, 2645. (d) Tan, Y.; Yuan, W.; Gong, L.; Meggers, E. Angew. Chem., Int. Ed. 2015, 54, 13045. (12) Yang, Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H. Angew. Chem., Int. Ed. 2017, 56, 3694. (13) Hou, H.; Zhu, S.; Atodiresei, I.; Rueping, M. Eur. J. Org. Chem. 2018, 2018, 1277. (14) (a) Rösner, M.; Billhardt-Troughton, U.-M.; Kirsh, R.; Kleim, J.-P.; Meichsner, C.; Riess, G.; Winkler, I. U.S. Patent 5,723,461, 1998. (b) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J. W.; Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370. (c) Ren, J.; Nichols, C. E.; Chamberlain, P. P.; Weaver, K. L.; Short, S. A.; Chan, J. H.; Kleim, J.-P.; Stammers, D. K. J. Med. Chem. 2007, 50, 2301. (d) Cass, L. M.; Moore, K. H. P.; Dallow, N. S.; Jones, A. E.; Sisson, J. R.; Prince, W. T. J. Clin. Pharmacol. 2001, 41, 528. (15) Tanimori, S.; Nishimura, T.; Kirihata, M. Bioorg. Med. Chem. Lett. 2009, 19, 4119. (16) Eary, C. T.; Jones, Z. S.; Groneberg, R. D.; Burgess, L. E.; Mareska, D. A.; Drew, M. D.; Blake, J. F.; Laird, E. R.; Balachari, D.; O’Sullivan, M.; Allen, A.; Marsh, V. Bioorg. Med. Chem. Lett. 2007, 17, 2608. (17) Chen, J. J.; Qian, W.; Biswas, K.; Viswanadhan, V. N.; Askew, B. C.; Hitchcock, S.; Hungate, R. W.; Arik, L.; Johnson, E. Bioorg. Med. Chem. Lett. 2008, 18, 4477. (18) Abu Shuheil, M. Y.; Hassuneh, M. R.; Al-Hiari, Y. M.; Qaisi, A. M.; El-Abadelah, M. M. Heterocycles 2007, 71, 2155. (19) (a) Carter, G. A.; Clark, T.; James, C. S.; Loeffler, R. S. T. Pestic. Sci. 1983, 14, 135. (b) Sakata, G.; Makino, K.; Kurasawa, Y. Heterocycles 1988, 27, 2481. (20) (a) Rueping, M.; Tato, F.; Schoepke, F. R. Chem. - Eur. J. 2010, 16, 2688. (b) Núñez-Rico, J. L.; Vidal-Ferran, A. Org. Lett. 2013, 15, 2066. (c) Shi, F.; Tan, W.; Zhang, H.-H.; Li, M.; Ye, Q.; Ma, G.-H.; Tu, S.-J.; Li, G. Adv. Synth. Catal. 2013, 355, 3715. (d) Chen, M.-W.; Deng, Z.; Yang, Q.; Huang, J.; Peng, Y. Org. Chem. Front. 2019, 6, 746. (21) Zhang, X.; Xu, B.; Xu, M.-H. Org. Chem. Front. 2016, 3, 944. (22) De Munck, L.; Vila, C.; Pons, C.; Pedro, J. R. Synthesis 2017, 49, 2683. (23) Rostoll-Berenguer, J.; Blay, G.; Pedro, J. R.; Vila, C. Catalysts 2018, 8, 653. (24) We observed the oxidation product 4.
CCDC 1922649 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Gonzalo Blay: 0000-0002-7379-6789 José R. Pedro: 0000-0002-6137-866X Carlos Vila: 0000-0001-9306-1109 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the Agencia Estatal de Investigación (AEI, Spanish Government) and Fondo Europeo de Desarrollo Regional (FEDER, European Union) (CTQ2017-84900-P) is acknowledged. J.R.-B. thanks the Ministerio de Ciencia, Innovación y Universidades for an FPU predoctoral contract, and C.V. thanks the Agencia Estatal de Investigación (AEI, Spanish Government) for an RyC contract (RYC-201620187). Access to NMR, MS, and X-ray facilities from the Servei Central de Suport a la Investigació Experimental (SCSIE)-UV is also acknowledged.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b02157 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters (25) When cycloheptanone was used as nucleophile the reaction was very slow and the product was observed with very low conversion after several days. (26) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260. (27) (a) Lin, J.-F.; Wu, C.-C.; Lien, M.-H. J. Phys. Chem. 1995, 99, 16903. (b) Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 1998, 120, 2768. (28) See Supporting Information for further details. (29) A crystal structure of a similar compound, racemic ethyl 2-(3oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)acetate, has been published: Abad, N.; Sebhaoui, J.; El Bakri, Y.; Ramli, Y.; Essassi, E. M.; Mague, J. T. IUCrData 2018, 3, x180596. (30) n-Butanal was tested as a nucleophile under the optimized reaction conditions, although the corresponding product was obtained in moderate yield (51%) without stereochemical control (1:1 dr, 0% ee: 0% ee).
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DOI: 10.1021/acs.orglett.9b02157 Org. Lett. XXXX, XXX, XXX−XXX
